ACE inhibitors, angiotensin receptor blockers yield similar efficacy, safety in patients without HF

Angiotensin receptor blockers are as safe and effective as ACE inhibitors in patients without heart failure, with the added advantage of better tolerability, according to an analysis of more than 250,000 patients from randomized trials.

Sripal Bangalore, MD, MHA, associate professor of medicine at New York University School of Medicine, told Cardiology Today that the objective of this analysis was to end the debate over which class of agents is associated with better outcomes for patients without HF.

Sripal Bangalore

“Many placebo trials have shown significant benefits with ACE inhibitors, while no such benefits were shown for angiotensin receptor blockers. Most of the time, positive trials can tend to have a long-lasting, lingering effect. Because of this, most physicians and many guidelines still consider ACE inhibitors to be superior, despite the fact that head-to-head trials comparing ACE inhibitors and angiotensin receptor blockers have shown similar outcomes,” he said.

To compare the efficacy and safety of angiotensin receptor blockers vs. ACE inhibitors, Bangalore and colleagues conducted a meta-analysis of 106 randomized trials that included 254,301 patients. Fifty-eight trials randomly assigned 126,025 patients to an ACE inhibitor vs. control (placebo or active); 42 trials randomly assigned 105,734 patients to an angiotensin receptor blocker vs. control (placebo or active); and eight trials randomly assigned 22,542 patients to an ACE inhibitor vs. an angiotensin receptor blocker.

The researchers analyzed relative risks for all-cause mortality, CV death, MI, angina, stroke, HF, revascularization, new-onset diabetes, end-stage renal disease, doubling of serum creatinine, hyperkalemia and drug withdrawal due to adverse events in all trials.

Compared with placebo, ACE inhibitors, but not angiotensin receptor blockers, were associated with reduced risk for:

all-cause mortality (RR = 0.91; 95% CI, 0.86-0.96)
CV death (RR = 0.85; 95% CI, 0.79-0.92)
MI (RR = 0.83; 95% CI, 0.78-0.9)
angina (RR = 0.93; 95% CI, 0.87-0.99)
stroke (RR = 0.85; 95% CI, 0.76-0.94)
HF (RR = 0.77; 95% CI, 0.71-0.84)
revascularization (RR = 0.93; 95% CI, 0.89-0.98)
new-onset diabetes (RR = 0.86; 95% CI, 0.79-0.93)
end stage renal disease (RR = 0.57; 95% CI, 0.44-0.74)
doubling of serum creatinine (RR = 0.62; 95% CI, 0.49-0.8)

There was however an increase in drug withdrawal due to adverse effects with ACE inhibitors (RR = 1.24; 95% CI, 1.19-1.29).

Compared with placebo, angiotensin receptor blockers were associated with reduced risk for:

stroke (RR = 0.91; 95% CI, 0.85-0.97)
HF (RR = 0.89; 95% CI, 0.82-0.96)
new-onset diabetes (RR = 0.89; 95% CI, 0.84-0.95)
end-stage renal disease (RR = 0.81; 95% CI, 0.7-0.94)
doubling of serum creatinine (RR = 0.86; 95% CI, 0.75-0.98)

To further investigate these findings, the researchers performed a meta-regression analysis. According to the results, the difference between the two agents was the result of a higher placebo event rate in the ACE inhibitor trials for all three outcomes: all-cause mortality (P = .001), CV death (P <.001) and MI (P = .02). Since most of the ACE inhibitor trials were conducted about a decade before the angiotensin receptor blocker trials, Bangalore and colleagues conducted sensitivity analyses on trials published after 2000, which revealed that angiotensin receptor blockers and ACE inhibitors had similar outcomes compared with placebo.

Both the active-control trials and head-to-head comparisons of the two agents revealed similar outcomes, except for drug withdrawal due to adverse effects. In the head-to-head comparison trials, angiotensin receptor blockers were associated with a 28% lower risk for withdrawal due to adverse effects compared with ACE inhibitors (RR = 0.72; 95% CI, 0.65-0.81).

“We found that the difference was a generation gap between the two trials,” Bangalore said. “In the 90s, patients’ personal choices were different. More people smoked. Guidelines and risk factor control were less aggressive. It was easier to show a benefit when the background risk was higher.”

Bangalore said the difference in tolerability between the two classes of agents may be related to the pathways. “ACE inhibitors increase bradykinin, which is thought to increase cough and other adverse effects. Angiotensin receptor blockers do not work on the bradykinin pathways — only on the receptors,” he said.

“Our hope is that this finally settles two decades of debate. We clearly show that there is no outcome difference between the two classes of agents. You can choose either one of them, but also bear in mind that tolerability might be an extremely important factor.” – by Tracey Romero

Disclosure: Bangalore reports receiving honoraria from Abbott, Boehringer Ingelheim, Daiichi Sankyo, Gilead, Merck and Pfizer. Please see the full study for a list of all authors’ relevant financial disclosures.

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Source: Bangalore S, et al. Mayo Clin Proc. 2015;doi:10.1016/j.mayocp.2015.10.019.